1. Field of the Invention
The present application concerns medical sciences and more particularly detection and treatment of human cancers, especially breast cancer.
2. Description of Related Art
Membrane associated heparan sulfate proteoglycans (HSPGs) are thought to play important roles in many aspects of cell behavior, including cell-cell and cell-extracellular matrix adhesion (59, 104) and growth factor signaling (13, 89). Two families of polypeptides appear to carry the majority of the heparan sulfate on mammalian cells: glypicans, which are attached to the plasma membrane via glycosylphophatidylinositol (GPI) anchors, and syndecans, which are transmembrane proteins (13, 7). Four syndecans and five glypicans, all encoded by separate genes, have been described to date (6, 14, 107, 23, 117 and 97). Many of these polypeptides exhibit tissue specific patterns of expression, although these patterns often overlap (38, 64, 2 and 9). In vitro, at least, it is common for cells to express multiple HSPGs, often from both the glypican and syndecan families.
The binding of heparin-binding growth factors to their cell surface receptors often requires the presence of cell-surface heparan sulfate proteoglycans (HSPGs) (27, 37, 90). There are two families of molecules, syndecans and glypicans, that differ significantly in core protein domain structure (13, 7). Five members of the glypican family (glypican-1-5) and four members of the syndecan family (syndecan-1-4) have been reported to date (64, 4). They have important functions with respect to cell behavior, including cell-cell and cell-extracellular matrix adhesion (59, 104), growth factor signaling (13, 89) and protection of growth factors such as FGF-2 from thermal denaturation and proteolytic attack (96, 102). They also regulate the interaction of several heparin-binding growth factors with their respective receptors and, consequently, their biological activity (99).
The role of HSPGs in growth factor signaling has been best characterized with respect to fibroblast growth factors (FGFs), which require the presence of heparan sulfate for high affinity binding to their tyrosine kinase receptors (88, 120, and 8). More recently, several other growth factors have been found to exhibit a strong requirement for an HSPG coreceptor in their signaling; these include heparin-binding EGF-like growth factor (HB-EGF), hepatocyte growth factor (HGF), and members of the Wnt family of secreted glycoproteins (27, 94, 37, and 90). Many other growth factors, including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), transforming growth factor-s (TGF-s), and bone morphogenetic proteins (BMPs), are known to bind heparin and heparan sulfate, although the physiological consequences of this binding are unclear.
Pancreatic cancer is responsible for over 20% of deaths due to gastrointestinal malignancies, making it the fourth to fifth most common cause of cancer related mortality. The prognosis of patients with pancreatic cancer is extremely poor, with 5-year survival rates lower than 5% (116). The reasons for this biological aggressiveness have not been clearly elucidated. Nonetheless, previous work has established that these cancers overexpress many mitogenic growth factors and their receptors (44) including a number of heparin-binding growth factors such as FGF1, FGF2, FGF5, HB-EGF, and amphiregulin. (119, 20, 4, and 48).
The mortality of breast cancer in the United States has recently leveled off and even decreased slightly (1, 2). However, breast cancer remains the second most common cause of cancer death in women in the United States (51). Breast cancer is expected to account for 192,200 new cancer cases in the United States in 2001, and more than 40,000 women are projected to die in 2000 from this disease (1). A variety of molecular alterations have been reported in breast cancer. These include loss of heterozygosity (1p, 3p, 7q, 11p, 17p, 17 and 18q), mutations (BCRA1,2, p53, c-H-ras-1), and /or gene amplifications (c-myc, c-erbB-2) (80, 35, 36, 60, 66, 70, 82, and 56). In the case of c-erbB-2, overexpression has been correlated with aggressive disease and decreased patient survival. Furthermore, anti-erbB-2 antibodies can suppress breast cancer cell growth in vitro and decrease tumor burden in vivo, thereby prolonging patient survival (91, 43, 6, and 77).
To date a ligand that binds to c-erbB-2 has not been identified (98, 71). Instead, c-erbB-2 is capable of heterodimerizing with the other members of the EGF receptor family once these receptors bind their ligands (98, 71, 119, and 115). These ligands include epidermal growth factor (EGF), transforming growth factor-alpha (TGF-), heparin-binding EGF-like growth factor (HB-EGF), betacellulin, amphiregulin (AR) and epiregulin. HB-EGF and amphiregulin are heparin-binding factors. In addition, breast cancers overexpress fibroblast growth factor-2 (FGF-2) and type1–4 FGF receptors (11), and hepatocyte growth factor (HGF) and its receptor (c-Met) (bc 19). Both FGF-2 and HGF are heparin-binding factors. Together, these observations suggest that multiple heparin-binding growth factors participate in the pathobiology of breast cancer in humans.
The binding of heparin-binding growth factors to their cell surface receptors often requires the presence of cell-surface heparan sulfate proteoglycans (HSPGs) (20, 22, 23). There are two main families of such molecules, syndecans and glypicans, that differ significantly in core protein domain structure (24, 25). Six members of the glypican family (glypican 1 through 6) and four members of the syndecan family (syndecan 1 through 4) have been reported to date (26–30). They have important functions with respect to cell behavior, including cell-cell and cell-extracellular matrix adhesion 31, 32), grwth factor signaling (24, 34) and protection of growth factors such as FGF-2 from thermal denaturation and proteolytic attack (35, 36). They also regulate the interaction of several heparin-binding growth factors with their receptors and, consequently, their biological activity (37).